Chesley's Hypertensive Disorders in Pregnancy (eBook)

Front Cover 1
Chesley's Hypertensive Disorders in Pregnancy 4
Copyright Page 5
Contents 6
List of Contributors 8
Preface 10
1 Introduction, History, Controversies, and Definitions 12
History (Fig. 1.1) 12
Signs 15
Edema 15
Proteinuria 15
Hypertension 16
Hypotheses and Rational Management 17
Prophylaxis 19
Classification of the Hypertensive Disorders in Pregnancy 20
Editors’ Update 22
Measurement of Blood Pressure 22
Classifications and Definitions: The American College of Obstetricians and Gynecologists Hypertension in Pregnancy Hyperten ... 24
Denouement 25
False Steps in the Study of Preeclampsia 25
References 31
2 The Clinical Spectrum of Preeclampsia 36
Introduction 36
Clinical Manifestations of Preeclampsia Syndrome 37
Cardiovascular System 37
Loss of Pregnancy Hypervolemia 38
Blood and Coagulation 39
The Kidney 39
The Liver 40
The Brain 43
Uteroplacental Perfusion 44
Differential Diagnosis 45
References 45
3 Epidemiology of Pregnancy-Related Hypertension 48
Introduction 48
Definitions of the Hypertensive Disorders of Pregnancy 48
Prevalence of Hypertensive Disorders of Pregnancy 49
Eclampsia 49
Preeclampsia 49
Discussion of Differential Frequency Estimates 51
Risk Factors for Preeclampsia 52
Cardiovascular Risk Factors 52
Body Mass Index 53
Physical Activity 53
Diet 54
Vitamin D 54
Smoking 54
Family Patterns 54
First Birth and Other Placental Factors 55
Clinical Predictors 56
Natural History 56
Maternal Morbidity Immediately Related to Preeclampsia 56
Recurrence of Preeclampsia in Subsequent Pregnancies 56
Reduced Risk of Later-Life Breast Cancer 56
Increased Risk of Later Life Cardiovascular Disease 56
Physiological Mechanisms Linking Preeclampsia to Maternal CVD Risk 57
Impact on Children 58
Perinatal Outcomes 58
Remote Impact on Cardiovascular Function in Offspring of Preeclamptic Pregnancies 59
Critique of Studies 59
Conclusion 59
Acknowledgment 59
References 59
4 Genetic Factors in the Etiology of Preeclampsia/Eclampsia 68
Dedication 68
Introduction 68
Biological Pathways of Preeclampsia 72
Fetal/Placental Components of Preeclampsia 73
Immunogenetic Factors (see also Chapter 8) 73
Types of Genetic Studies Conducted 74
Family Reports 74
Twin Studies 74
Segregation Analyses 75
Linkage Analyses 76
Association Studies 77
Genome-Wide Association Studies (GWAS) 80
Next-Generation Sequencing 81
A Genomics Approach to Preeclampsia 81
Essential Variables to Consider 83
Interacting Genomes 83
Subgroups 83
Genomic Ethnicity 83
Population Size 84
Gene–Gene Interactions 84
Epigenetics 85
Gene–Environment Interactions 85
Confounding Variables 85
High-Dimensional Biology 86
A Predictive Genetic Test 86
Pharmacogenomics 86
The Future of Preeclampsia Genetic Research 86
Conclusions 86
References 87
5 The Placenta in Normal Pregnancy and Preeclampsia 92
APPENDIX: Trophoblast Gene Expression in Normal Pregnancy and Preeclampsia 106
6 Angiogenesis and Preeclampsia 124
Introduction 124
Placental Vascular Development in Health 124
Placental Vasculogenesis 124
Maternal Vascular Remodeling 125
Fetal Circulation and Placental Villous Angiogenesis 125
Angiogenic Factors and Placentation 127
Natural Killer Cells and Placental Vascular Development 128
Angiogenic Imbalance in Preeclampsia 129
Soluble Antiangiogenic Factors in Preeclampsia 129
Upstream Pathways and Mechanisms of Preeclampsia 134
Angiogenesis and the Remote Consequences of Preeclampsia 135
Role of Angiogenic Biomarkers in Preeclampsia 135
Therapeutic Strategies for Preeclampsia 135
Anti-Angiogenic Versus Normal Angiogenic Forms of Preeclampsia 136
Perspectives 136
References 137
7 Metabolic Syndrome and Preeclampsia 144
Introduction 144
Metabolic Syndrome 145
Metabolic Syndrome and Cardiovascular Disease 146
Obesity 146
Free Fatty Acids and TNF-a 147
Renin-Angiotensin System 149
Adipocyte Hypertrophy and Endoplasmic Reticulum Stress 150
Pregnancy-Induced Metabolic Changes 150
Carbohydrate and Lipid Metabolism 150
Maternal Weight Gain in Pregnancy 151
Preeclampsia and Metabolic Syndrome 152
Obesity and Insulin Resistance 152
Inflammation 153
Dyslipidemia 155
Angiogenic Factors 156
Uric Acid and ADMA 157
Lifestyle Factors 157
Later-Life Cardiovascular Risk (also see Chapter 3) 158
Metabolic Syndrome: a Cause of Placental Dysfunction? 159
Summary and Perspectives 161
References 162
8 Immunology of Normal Pregnancy and Preeclampsia 172
Introduction 172
Maternal Adaptation to a Foreign Fetus 172
Innate and Adaptive Immunity 173
Nature’s Transplant 173
Classical Two-Stage Model of Preeclampsia 174
Stage 1 Preeclampsia, Interface 1 and Maternal Immune Responses to Trophoblast 176
Stage 2 Preeclampsia and Interface 2 176
Endothelial Cells are Inflammatory Cells 177
Inflammation and the Integrated Stress Response 177
Widespread Implications of Vascular Inflammation 177
Cytokines, Chemokines, Growth Factors, Adipokines and Angiogenic Factors 178
Metabolism and Vascular Inflammation 178
Acute-Phase Response 179
Vascular Inflammation in Normal Pregnancy and Preeclampsia 179
The Continuum Between Normal Pregnancy and Preeclampsia 180
Immunoregulation 180
T Regulatory Cells, Th17 and T-Cell Memory 180
Normal Pregnancy 180
Angiotensin II (Ang II), the Immune System and Preeclampsia 181
Systemic Immunoregulation in Normal Pregnancy and Preeclampsia 181
Acute Atherosis: A Second Inflammatory Lesion of Preeclampsia 182
The Role of the Placenta and Non-Placental Factors 182
Trophoblast Extracellular Vesicles 184
Maternal Predisposing Factors 184
Conclusions 186
References 186
9 Endothelial Cell Dysfunction 192
Introduction 192
Part I: Endothelial Cell Function and Preeclampsia 193
Endothelial Cell Dysfunction in Preeclampsia 193
Circulating Markers of Endothelial Cell Activation 194
Growth Factor Binding Proteins in Preeclampsia 195
Part II: Circulating Factors Induce Endothelial Cell Dysfunction 195
Formed Elements in Blood as Activators of Endothelium 195
Placental Membrane Microvesicles 196
Endothelial Progenitor Cells (EPCs) 196
Immune Complexes: Antiphospholipid and Antiendothelial Cell Antibodies 196
Cytokines 197
Circulating Lipids and Lipoproteins 198
Non-Esterified Fatty Acids 198
Peroxisome Proliferator-Activated Receptors (PPARs) 199
Angiogenic Factors 200
Matrix Metalloproteinases 200
Endothelin 201
Relaxin 202
Angiotensin II 202
Toll-Like Receptors 202
Part III: Oxidative Stress: A Point of Convergence for Endothelial Cell Dysfunction 202
Oxidative Stress as a Mediator of Endothelial Cell Dysfunction 202
Eicosanoid/Prostacylin Production 203
Nitric Oxide 204
Endothelium-Derived Hyperpolarization 205
Other Vasodilators 205
Part IV: Clinical Trials 206
Aspirin 206
L-Arginine 206
Fish Oil 206
Calcium 207
Anticoagulants 207
Summary 207
Part V: Speculations and Directions of Future Investigations 207
References 208
10 Animal Models for Investigating Pathophysiological Mechanisms of Preeclampsia 220
Introduction 220
Models Used to Investigate Links Between Placental Ischemia and Endothelial and Cardiovascular Dysfunction 220
Animal Models Used to Study Role of Angiogenic Factors (See Also Chapter 6) 223
Models Used to Investigate the Role of Immune Mechanisms in Preeclampsia 224
Genetic Models 225
BPH/5 225
Genetic Modification of the Renin-Angiotensin System 226
STOX1 Overexpression 226
COMT Knockout 227
Potential Models with Placental Abnormalities 227
Summary 228
References 228
11 Tests to Predict Preeclampsia 232
Introduction 232
Assessing the Quality of Tests to Predict Disease 232
Placental Perfusion and Vascular Resistance Dysfunction-Related Tests 234
Roll-Over Test, Isometric Exercise Test, and Angiotensin II Sensitivity Test 234
Blood Pressure 235
Transcranial Doppler Velocimetry 235
Uterine Artery Doppler Velocimetry 236
Fetal and Placental Unit Endocrinology Dysfunction-Related Tests 237
Human Chorionic Gonadotropin 237
Alpha Fetoprotein 237
Estriol 237
Inhibin A 239
Pregnancy-Associated Plasma Protein A 239
Activin A 239
Placental Protein 13 239
A Disintegrin and Metalloprotease 12 239
Renal Dysfunction-Related Tests 240
Serum Uric Acid 240
Microalbuminuria 240
Urinary Calcium Excretion 240
Urinary Kallikrein 240
Podocyturia (See Chapter 16) 240
Endothelial Dysfunction and Oxidant Stress-Related Tests 241
Fibronectin 241
Homocysteine 241
Endothelial Cell Adhesion Molecules 241
Circulating Angiogenic Factors 242
Other Tests 243
Cell-Free Fetal Deoxyribonucleic Acid 243
Proteomic, Metabolomic, and Transcriptomic Markers 245
The Use of Combined Tests 246
Multivariable Prediction Models Derived from Combinations of Maternal Characteristics and Tests 249
Perspectives and Conclusions 252
Acknowledgement 255
References 255
12 Prevention of Preeclampsia and Eclampsia 264
Introduction 264
Dietary Manipulations 265
Low-Salt Diet 265
Fish Oil 265
Calcium Supplementation 266
Physical Activity 267
Diuretics and Antihypertensive Drugs 267
Antioxidant Vitamins 268
Antithrombotic Agents 268
Low-Dose Aspirin 269
Low-Dose Aspirin Plus Heparin 270
Statins 270
Prevention of Eclampsia 270
Magnesium Sulfate for Mild Preeclampsia 270
Magnesium Sulfate for Severe Preeclampsia 271
Effects of Magnesium Sulfate on Maternal Mortality and Morbidity 272
Effects of Magnesium Sulfate on Perinatal Mortality and Morbidity 273
Treatment for Eclampsia (See Chapter 20) 273
Side Effects and Toxicity 274
Initiation, Dose, Duration, and Route of Administration 274
Prevention of Long-Term Maternal Health Risks Following Preeclampsia 275
References 276
13 Cerebrovascular Pathophysiology in Preeclampsia and Eclampsia 280
Introduction 280
Neuroanatomical Findings with Eclampsia 281
Neuroimaging in Eclampsia 281
Computed Tomography (CT) 281
Magnetic Resonance Imaging (MRI) 282
Diffusion-Weighted MRI and Apparent Diffusion Coefficient 283
Pathogenesis of Cerebral Manifestations in (PRE)eclampsia 284
Eclampsia as Posterior Reversible Encephalopathy Syndrome (PRES) 285
Cerebral Blood Flow Autoregulation 285
Cerebral Blood Flow Autoregulation and Hemodynamics in Pregnancy 286
Animal Studies 286
Human Studies 287
Mechanisms of Seizure During Pregnancy and Preeclampsia 290
Role of Circulating Factors in Eclampsia 291
Blood–Brain Barrier 291
Aquaporins and Cerebral Edema During Pregnancy 293
Effect of Magnesium Sulfate Treatment 293
Cerebral Hemorrhage 294
Cortical Blindness 294
Remote Cerebrovascular Health Following Preeclampsia and Eclampsia 294
Visual Functioning 294
Brain White Matter Lesions 294
Neurocognitive Functioning 296
Epilepsy 296
Stroke 296
References 296
14 Cardiovascular Alterations in Normal and Preeclamptic Pregnancy 302
Introduction 302
Hemodynamics and Cardiac Function in Normal Pregnancy 302
Systemic Arterial Hemodynamics in Normal Pregnancy 302
Venous System in Normal Pregnancy 304
Systemic Arterial Properties in Normal Pregnancy 305
Left Ventricular Properties in Normal Pregnancy 306
Coupling between Left Ventricle and Systemic Arterial Circulation in Normal Pregnancy 308
Hemodynamics and Cardiac Function in Preeclampsia 308
Systemic Arterial Hemodynamics in Preeclampsia 308
Systemic Arterial Properties in Preeclampsia 311
Left Ventricular Properties in Preeclampsia 313
Factors that May Explain Vascular Changes in pregnancy 315
Normal Pregnancy 315
Preeclampsia 317
Pregnancy-Associated Responses and the Assessment of Cardiovacular Disease Risk Later in Life 317
Summary 318
References 319
15 The Renin-Angiotensin System, its Autoantibodies, and Body Fluid Volume in Preeclampsia 326
Introduction 326
Body Fluid Volumes 327
Preeclampsia 328
“Normal Fill” or Resetting of the “Volumestat” 328
Primary Arterial Vasodilatation (“Underfill”) 329
Excessive Expansion or “Overfill” 329
Plasma Volume in Normal Pregnancy and Preeclampsia 330
Novel Salt Concept 331
Mineralocorticoids and the Renin-Angiotensin-Aldosterone Axis 332
Antinaturetic Peptides in Pregnancy 334
Preeclampsia 334
Agonistic Anti-AT1 Receptor Antibodies 335
Agonistic Anti-AT1 Receptor Antibodies in Preeclampsia (AT1-AA) 336
Signal Transduction and Pathophysiological Role of AT1-AA 336
AT1-AA in Animal Models of Hypertension During Pregnancy (See also Chapter 10) 337
AT1-AA Induced Hypertension 339
Presence of AT1-AA in Other Diseases 340
Concluding Perspectives 341
References 341
16 The Kidney in Normal Pregnancy and Preeclampsia 346
Introduction 346
Renal Hemodynamics and Glomerular Filtration Rate During Normal Pregnancy 346
Renal Clearances of para-Aminohippurate and Inulin 347
Creatinine Clearance 348
Postural Influences on Renal Function 349
Mechanisms for Alterations of Renal Hemodynamics and GFR 349
Cellular and Molecular Mechanisms of Renal Vasodilatation 352
Osmoregulation in Normal Pregnancy 356
Renal Hemodynamics and Glomerular Filtration Rate in Preeclampsia 357
Summary 361
Renal Handling of Uric Acid 362
Normal Pregnancy 362
Preeclampsia 363
Summary 367
Renal Handling of Proteins 368
Normal Pregnancy 368
Preeclampsia 369
Summary 373
Renal Morphology in Pregnancy and Preeclampsia 373
Introduction 373
Gross Morphology 374
Indications for Renal Biopsy in Pregnancy 378
References 379
17 Platelets, Coagulation, and the Liver 390
Introduction 390
Platelets 390
Platelets in Normal Pregnancies and with Preeclampsia 391
Platelet Activation In Vivo 393
Summary of Platelet Activation 393
Platelet Behavior In Vitro 394
Expression of Platelet Receptors in Pregnancy and Preeclampsia 394
Platelet Second Messengers 395
Platelet Angiotensin II-Binding Sites 395
Coagulation 396
Coagulation Cascade Factors 396
Regulatory Proteins and Thrombophilia 397
Fibrinolytic System 398
Fibrinolysis in Normal Pregnancy 399
Fibrinolysis in Preeclampsia 399
The Liver in Preeclampsia 399
Clinical Aspects of Liver Involvement 400
The Liver in HELLP Syndrome 401
Corticosteroid Therapy for HELLP Syndrome 402
References 402
18 Chronic Hypertension and Pregnancy 408
Introduction 408
Background 408
Definition 408
Diagnosis 409
Cardiac and Hemodynamic Alterations 409
Effect of Chronic Hypertension on the Mother 410
Effects of Chronic Hypertension on Fetal/Neonatal Outcome 411
Chronic Hypertension with Superimposed Preeclampsia 411
Effects of Superimposed Preeclampsia on the Mother and Fetus/Neonate 412
Specific Hypertensive Disorders 413
Essential Hypertension 413
Physiology and Pathophysiology of Essential Hypertension During Pregnancy 414
Blood Pressure Patterns and Hemodynamic Measurements 414
Hormonal and Biochemical Alterations 415
Pathophysiology of Superimposed Preeclampsia 415
Secondary Hypertension 416
Renal Disease 416
Renovascular Hypertension 416
Primary Aldosteronism 417
Pheochromocytoma 419
Cushing Syndrome 420
Postpartum Hypertension 420
Management Principles 421
Preconception Counseling 421
Non-Pharmacologic Management 422
Pharmacologic Management (see Chapter 19) 422
References 423
19 Antihypertensive Treatment 430
Introduction 430
Goals of Antihypertensive Drug Therapy 430
General Principles in the Choice of Antihypertensive Agents 431
Fetal Safety and Drug use in Pregnant Women 432
Choice of an Antihypertensive Drug for use in Pregnancy 433
Sympathetic Nervous System Inhibition 433
Centrally Acting a2-Adrenergic Agonists 433
Peripherally Acting Adrenergic-Receptor Antagonists 435
Diuretics 436
Calcium-Channel Antagonists 437
Direct Vasodilators 438
Modulators of the Renin–Angiotensin–Aldosterone Axis 439
Drug use While Breastfeeding 440
Evidence from Randomized Trials 441
Evidence for Antihypertensive Treatment in Mild to Moderate Hypertension 441
Evidence for Antihypertensive Treatment in Severe Hypertension 443
Conclusion 443
References 445
20 Clinical Management 450
Introduction 450
Preeclampsia 450
Early Diagnosis and Evaluation 450
Hospitalization Versus Outpatient Management 451
Antihypertensive Therapy for Mild to Moderate Hypertension 452
Indications for Delivery 454
Delayed Delivery with Early-Onset Preeclampsia 455
Eclampsia 458
Immediate Management of Seizure 459
Medical Treatment of Eclampsia 459
Management of Severe Hypertension 463
Commonly Used Antihypertensive Agents 463
Other Antihypertensive Agents 465
Diuretics 465
Fluid Therapy 465
Pulmonary Edema 465
Plasma Volume Expansion 466
Neuroprophylaxis – Prevention of Eclampsia 466
Who Should Be Given Magnesium Sulfate? 467
Delivery 468
Blood Loss at Delivery 468
Analgesia and Anesthesia 469
Persistent Severe Postpartum Hypertension 470
Furosemide 470
References 471
Index 476